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Randomization
Randomization is the process of assigning clinical trial participants to treatment groups. Randomization gives each participant a known (usually equal) chance of being assigned to any of the groups. Successful randomization requires that group assignment cannot be predicted in advance.
Why Randomize?
If, at the end of a clinical trial, a difference in outcomes occurs between two treatment groups (say, intervention and control) possible explanations for this difference would include: the intervention exhibits a real effect; the outcome difference is solely due to chance there is a systematic difference (or bias) between the groups due to factors other than the intervention.
Randomization aims to obviate the third possibility.
Forms of Randomization
Simple Randomization Permuted Block Randomization Stratified Block Randomization Dynamic (adaptive) random allocation
Simple Randomization
Coin Tossing for each trial participant Sequence of Random Numbers from statistical textbooks Computer generated sequence
Illustrations
The computer generated sequence: 4,8,3,2,7,2,6,6,3,4,2,1,6,2,0,. Two Groups (criterion:even-odd): AABABAAABAABAAA Three Groups: (criterion:{1,2,3}~A, {4,5,6}~B, {7,8,9}~C; ignore 0s) BCAACABBABAABA Two Groups: different randomisation ratios(eg.,2:3): (criterion:{0,1,2,3}~A, {4,5,6,7,8,9}~B) BBAABABBABAABAA..
Illustration
With a block size of 4 for two groups(A,B), there are 6 possible permutations and they can be coded as: 1=AABB, 2=ABAB, 3=ABBA, 4=BAAB, 5=BABA, 6=BBAA Each number in the random number sequence in turn selects the next block, determining the next four participant allocations (ignoring numbers 0,7,8 and 9). e.g., The sequence 67126814. will produce BBAA AABB ABAB BBAA AABB BAAB. In practice, a block size of four is too small since researchers may crack the code and risk selection bias. Mixing block sizes of between 6 and 12 is better with the size kept unknown to the investigator. This precaution maintains concealment. Simple randomization should determine which block size to use next.
Example of randomization using the minimisation method in a trial of chemotherapy for breast cancer, with stratification factors of clinic site, estrogen receptor status (ER+ or ER) and menopausal status
Characteristic
Treatment A
Treatment B
Site 1 7 8 Site 2 10 9 ER+ 5 6 ER 12 11 Premenopausal 8 9 Postmenopausal 9 8 Total 17 17 The next participant (no. 35) is from Site 2, ER+, postmenopausal. Subtotals for treatment allocation to this profile of characteristics are 10 + 5 + 9 = 24 for Treatment A and 9 + 6 + 8 = 23 for Treatment B (note subjects are counted more than once). Participant no. 35 would therefore be allocated to Treatment B. When the tallies on A and B are equal within a profile, the next participant is randomly allocated. This process is equivalent to a permuted block size of two within the profile.
Allocation Concealment
It is very important that those responsible for recruiting people into a trial are unaware of the group to which a participant will be allocated, should that subject agree to be in the study. This avoids both conscious and unconscious selection of patients into the study. For multicentre clinical trials, central randomization by telephone, interactive voice response system, fax or the Internet are ideal methods for allocation concealment. The clinician or data manager at the participating site assesses eligibility, gains consent, and makes the decision to enroll a patient, then calls the randomization service to get the treatment allocation. For single-centre clinical trials, it is usually possible to identify a staff member not involved with the trial who can keep the randomization list or envelopes. They should be instructed to keep the list private, and to only reveal a treatment allocation after receiving information demonstrating that the patient is eligible and has consented to the trial. In situations where remote randomization may not be feasible or desirable, a set of tamper-evident envelopes may be provided to each participating site. The envelopes should look identical, and each should have the trial identification and a sequential number on it. Inside is the treatment allocation and usually a trial identifier for the patient (e.g., unique sequential number). After assessing eligibility and consent, the next envelope in sequence is opened. Care needs to be taken that the envelopes are opaque and well sealed, and that the sequence of opening the envelopes is monitored regularly.
Bias
Bias is said to have occurred if the results observed reflect other factors in addition to (or even instead of) the effect of the treatment: Some potential sources of bias: Patient bias Care Provider bias Assessor bias Laboratory bias Analysis and Interpretation bias
Patient Bias
the patient's knowledge that the patient is receiving a "new" treatment may substantially affect the patient's subjective assessment there is a subject x disease interaction in at least some diseases (and virtually all diseases)
thus, the patient's knowledge of the treatment being received may affect the outcome of the study
Assessor Bias
the assessor's knowledge of which treatment the patient is receiving may affect the way the assessor assesses outcome such a bias would directly affect the validity of the conclusions of the study if the assessment is done while the patient is still receiving treatment, this may provide the patient with information about the treatment being received
Laboratory Bias
the knowledge of which treatment the patient received may affect the way in which the test is run or interpreted, or be retested. although this is most severe with subjectively graded results (pathology slides, photographs, ECG, etc.), this can also be a problem with "objective tests" such as laboratory assays which may be run subtly differently by the technician.
Blinding
All of these potential problems can be avoided if everyone involved in the study is blinded to the actual treatment the patient is receiving.
Blinding (also called masking or concealment of treatment) is intended to avoid bias caused by subjective judgment in reporting, evaluation, data processing, and analysis due to knowledge of treatment.
Hierarchy of Blinding
open label: no blinding
single blind: patient (usually;occasionally may be assessor) blinded to treatment double blind: patient and assessors (who often are also the health care providers and data collectors) blinded to treatment complete blind: everyone involved in the study blinded to treatment
However, even these applications may be substantially biased by knowledge of the treatment given and may result in toxicity over (or under) reported efficacy over estimated
Even a small fraction of patients assigned at random to placebo will reduce these potential problems substantially.
justification is usually that double-blind is "impractical" because of need to adjust medication, medication affecting laboratory values, potential side effects, etc. a single blind study should be used only when it would be unacceptable ethically to give an appropriate placebo treatment to a patient, and in such a case, the assessor (not the patient) should be the one blinded to the treatment
Double Blinding:Techniques
Coded treatment groups Placebo for each possible treatment - tablets identical in physical appearance - tablets with similar taste and smell - IV infusions would normally be the same carrier as used for active medications Other treatments "shammed" as far as possible: minimal power ultrasound therapy when testing effect of physical therapy in back pain breathing exercises when assessing the effect of conditioning exercises
Complete Blinding
probably the best approach which can be used, but requires two groups for data processing, one group to encode the data/analysis and one group to perform the analysis normally only available in major drug company studies, and not routinely used even then
Complete Blinding:Techniques
analysis uses coded treatment groups analysis uses coded side effects (e.g., side effects coded using non-standard scheme, with only numeric codes available at time of analysis) analysis uses coded laboratory tests (e.g., name of test coded numerically at time of analysis, using non-standard code)